Immune modulation in conjunction with tumor antigen presentation is a promising approach for optimizing the efficacy of cancer gene therapy protocols for metastatic cancer or minimal residual disease. In tumor vaccine strategies, cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are employed to recruit antigen-presenting cells, including dendritic cells and macrophages, which result in the activation of cytotoxic T lymphocytes (CTL) against proteins expressed by cancer cells (Warren and Weiner, 2000; Kim et al., 2000). GM-CSF induces activation, proliferation, and differentiation of a variety of immunologically active cell populations, thereby facilitating the development of both humoral and cellular-mediated immunity (Warren and Weiner, 2000). One promising vaccine approach involves the insertion of the GM-CSF gene into autologous cancer cells that are then used for immunization (Jaffee, 1999; Suh et al., 1999). These genetically engineered tumor cells produce the GM-CSF protein in the local environment of tumor cells, thereby activating the patients T cells, which then function to eradicate the cancer at metastatic sites. Whether delivered as genetically engineered tumor cells or as the soluble GM-CSF protein, the cytokine must be present in the same site as the vaccine component (Mellstedt et al., 1999). Indeed, the establishment of specific and long lasting antitumor immunity following vaccination with GM-CSF tumor cells requires the simultaneous presence of GM-CSF and tumor antigens at the vaccination site (Nagai et el., 1998). However, in spite of the therapeutic potential demonstrated in animal models and early-phase clinical trials, the clinical development of these protocols has been limited by difficulties relating to the establishment of autologous tumor cell cultures (Fong et al., 2000) and the performance of individualized gene transfer procedures ex vivo (Borrello et al., 1999). Alternatively, local delivery of GM-CSF by direct intratumoral injection, as well as paracrine secretion by genetically engineered cells, has been shown to be more effective in upregulating lymph node sensitization when compared to systemic administration (Kurane et al., 1997).
A novel cancer immunotherapy approach for metastatic cancer would exploit the potential of systemically administered matrix-targeted retroviral vectors, infused sequentially intravenously, to efficiently deliver both a cytokine gene and/or a cytocidal construct to tumor cells and associated tumor vasculature. The efficacy of matrix-targeted gene delivery has been demonstrated in models of liver metastasis (Gordon et al., 2000a) and subcutaneous human cancer xenografts in nude mice (Gordon et al., 2000b). The present invention provides targeted retroviral paticles, for systemic administration, carrying one or more cytokine genes that provide high level efficiency of cytokine gene delivery into a tumor and recruitment of host mononuclear cells (tumor infiltrating lymphocytes) into the tumor.